Targeting S1P receptors to prevent hearing loss Cochlear hair cells, the primary functional subunits required for the transduction of vibration into the auditory sensation, are subject to irreversible degeneration and consequent loss of hearing acuity. Hair cell loss occurs as the result of a number of insults, including exposure to prolonged, excessive noise, exposure to toxic drugs, and the inevitable process of senescence. Currently, there are no available therapies to prevent these degenerative processes other than minimizing exposure to damaging conditions. Our previous work has demonstrated that sphingosine 1-phosphate (S1P) signaling plays an important role in the maintenance of hair cell integrity. S1P is a small signaling lipid that specifically agonizes a family of five G protein coupled receptors (S1P1-5). Loss of the receptor known as S1P2 in a knockout mouse model results in progressive degeneration of cochlear and vestibular hair cells, balance defects, and profound deafness. Our data demonstrate that other receptors, including S1P3, are also involved in hair cell survival. In this proposal, we will test the hypothesis that S1P receptor agonism can prevent induced hair cell loss. Two aims will address this hypothesis. Aim 1 will identify all the S1P receptors involved in hair cell survival. This will be approached by careful analysis of knockout mice for each S1P receptor subtype. This information is necessary to pursue the most innovative and risky part of the proposal in Aim 2, which is identification and validation of agonists against the involved receptor subtypes identified in Aim 1 to prevent hair cell death. We have already developed major tools for this proposal including S1P receptor knockouts as well as cell-based assays for screening for S1P receptors. However, the risk will be in identifying proof-of-concept compounds - using the Molecular Libraries Screening Centers Network (MLSCN), or the TSRI-Florida screening facilities - and using them to prevent hearing loss. Importantly, proof-of-concept data derived from these studies could one day lead to medicines that could prevent or limi hearing loss. PUBLIC HEALTH RELEVANCE: Non-congenital hearing loss occurs when auditory hair cells die in the inner ear and can be caused by noise, infection, ototoxic medications or aging. Asymmetric hearing loss or death of vestibular hair cells can also lead to balance defects, such as vertigo. Currently there are no medicinal treatments for reversing hearing loss, and sensory hair cells do not regenerate. This proposal will study the function of a small lipid known as sphingosine 1-phosphate (S1P) in the inner ear. Loss of S1P signaling was recently shown to lead to degeneration of auditory and vestibular hair cells leading to hearing loss and disrupted balance in mice, suggesting S1P may play a protective role. Through a combination of neuroscience, genetics and pharmacology, this study aims to test the hypothesis that induced hearing loss can be prevented by pharmacological activation of specific S1P receptors. The goal of this research is to identify novel chemicals that can prevent hair cell loss that results from ototoxic drugs, or loud noise exposure in mouse models. Such findings may eventually lead to new medicines that could prevent hearing loss.